Cyclic imino-derivatives, mixtures of isomers, enantiomers, diastereomers, or a physiologically tolerated salt having antithrombotic action

 

(57) Abstract:

Usage: as substances with protivotrevozhnym action. The inventive product of cyclic imino-derivatives of General formula B-X-A-Y-E, where And unsubstituted or substituted 2-pyrrolidinone or pyrrolin-2-he; unsubstituted or substituted amino, aminomethyl or amidino or two nitrogen atom of amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate; Y-E substituted unbranched C2-5-alkyl, substituents which may be substituted; X is a group of formula-X1-X2-X3-X4-X5- where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl, imino, etc. X2non-branched C2-4-alkylene, C2-3-albaniles, and the double bond must not be adjacent to the heteroatom, unsubstituted or substituted phenylene; X3bond or-CO-, -CO-NH - or-NH-CO-, if X3not directly followed by a heteroatom or a triple bond balance; X4communication, non-branched C1-5-alkylen, nezamedin inntrengeren or naftilan, floortile etc. X5bond, mixtures of isomers, enantiomers, diastereomers, or a physiologically tolerated salt. table 1.

The invention relates to new cyclic imino-derivatives of General formula

In X And Y E (I) where a 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1means phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetaminophe, alkyl with 1-4 carbon atoms, substituted by two phenyl groups, cyclohexyl, naptalam or phenyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, moreover, these substituents are not in the position I, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, piperidinylcarbonyl or morpholinomethyl; or carbonyl, substituted stands, phenyl, methoxymethyl, amino group, methylaminopropane, arylaminopoly, AMI - nomation, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of the cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A, R2alkyl with 1-4 carbon atoms, unsubstituted or substituted phenyl;

In amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano, one or two alkyl groups with 1-4 carbon atoms, alkoxycarbonyl with the total number of carbon atoms 2-5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y-E nonbranched alkyl with 2-5 carbon atoms, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1,2-Diocletian, carboxyla, phosphonopropyl, 0-methylphosphono, 0,0-dimethy what sikabonyi, (2-morpholinoethyl)-oxycarbonyl, [2-(2 - oxo-1-pyrrolidinyl)-ethyl-]oxycarbonyl, generalquartiermeister with 1-3 carbon atoms in the CNS group, which phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted by alkyl with 1-4 carbon atoms, biphenyloxy, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

-X1X2X3X4X5where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -NH-, -NH-CO - or-NH-SO2- or between methylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of a, And X5with the rest IN;

X2nonbranched alkylen with 2-4 carbon atoms, albaniles with 2 or 3 carbon atoms and the double bond must not be adjacent to g is agropol, acetaminophe, methanesulfonylaminoethyl, methylsulfonyl, methylsulfinyl, methylsulfonyl, two methyl groups, cycloalkyl with 4-7 carbon atoms or bicycloalkyl to 7 carbon atoms;

X3bond, -CO-, -CO-NH -, or-NHCO-, if X3not directly followed by a heteroatom or a triple bond balance, and CO -,- CONH - and-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, the unbranched alkylene with 1-5 carbon atoms, phenylene, unsubstituted or substituted by fluorine, chlorine or stands, cycloalkyl with 4-7 carbon atoms;

X2together with X3and X4forms the unbranched alkylene with 3-6 carbon atoms, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or serialkiller from 8 to 11 carbon atoms;

X5link.

ture and/or diastereomers.

The mixture of CIS - and TRANS-isomers can be divided into separate CIS - and TRANS-isomers by chromatography, and the resulting compounds of General formula I present in the form of the racemates, can be divided into their optical antipodes by known method, and the resulting compounds of General formula I, with at least two asymmetric carbon atoms can be divided into their diastereomer in a known manner on the basis of their physical and chemical differences, for example, by chromatography and/or fractional crystallization. If the diastereomers are in the form of the racemates, can in this way be separated into the enantiomers.

The separation of enantiomers is preferably carried out by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reacting with an optical active substance, forming a salt with matematicheski connection, in particular with acid, and separating the thus obtained mixture of the diastereomeric salts, for example, due to different solubility, and from the pure diastereomeric salts by treatment with a suitable substance you can get free antipodes. Commonly used optically active acid is the notes, almond acid, camphor sulfonic acids, glutamic acid, aspartic acid or Hinn acid.

In addition, the compounds of General formula I with inorganic or organic acid can be converted to their acid additive salts, particularly for pharmaceutical use into the physiologically tolerated salts. The acid can be used, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The biological activity of compounds of General formula I were investigated as follows:

1. The binding of fibrinogen to platelets person.

Extracted by puncture antecubital veins the blood of trapping the clotting process triatriatum (final concentration of 13 mm) and centrifuged at 170 g for 10 minutes platelet-Rich plasma is fed to the column Sefiros 2B (firm Pharmacia, Sweden) and elute with a solution of 90 mm sodium chloride,14 mm triacrylate, 5 mm glucose and 50 mm Tris(oxymethyl)aminomethane, brought to a pH of 7.4. For experiments svyazyvanii gel-filtered platelets add 50 ál solution 60 mm of calcium chloride, 50 μl of a solution of 0.6 mm adenosine diphosphate, 100 μl of a solution of the substance or solvent and 50 μl of a solution of fibrinogen containing 3 µg 125-J-fibrinogen. Incubated at room temperature for 20 min, and Nonspecific binding determined in the presence of 3 mg per ml of cold fibrinogen.

Product incubation (900 ml) using a pipette, carefully served on 250 μl of silicone oil (a mixture of commercial products AR 38 AR 20 in a volume ratio 1 2 Wacker Chemie), placed in Eppendorf vessels, and centrifuged at 10 000 g for 2 minutes Vodou phase and part of the oil selected syringe, the tip of the syringe containing the platelets, cut and using a gamma counter to determine the amount of bound fibrinogen. On several samples with different concentrations of the substance to determine the concentration at which the substance inhibits the binding of fibrinogen to 50% (concentration braking CT50).

2. Antithrombotic effect.

Method. Aggregation is determined by the method of born and Cross on platelet-rich plasma of healthy people. For keeping the clotting of the blood type 3,14% sodium citrate in a volume ratio of 1:10.

Induced collagen aggregation. The decrease subsequent aggregation substance. The rate of aggregation is determined on the basis of the angle of inclination of the density curve. The point of the curve, showing the highest light transmission, serves to rasschityvaet optical density. The amount of collagen choose more small, but sufficient for irreversible reaction curve. Use commercially available collagen firm Harmonee, , Munich. Before adding collagen plasma together with a test compound are incubated at 37aboutC for 10 min.

Based on these results graphically determine the effective dose ED50, i.e. the dose at which achieved 50% change in optical density in terms of inhibition of aggregation. The results of the experiment are shown in table.

In addition, collagen-induced platelet aggregation ex vivo in rhesus macaque for more than 8 h delay, for example, the compound of example 70 (1), its subjects through the mouth in the amount of 1 mg/kg

The new compounds possess well tolerated by the body. Approximate LD50(lethal dose) of the compound of example 7 (3) in rats at intravenous supply greater than 100 mg/kg, and the estimated LD50the compound of example 70 (1), also in rats when applying through the mouth exceeds 2000 mg/kg

For the treatment and prophylaxis of these diseases, the compounds used in doses between 0.1 and 30 μg per kg body weight, preferably 1-15 µg per kg body weight, at 1-4 doses per day. The new compounds of General formula I can be converted to known drugs, such as tablets, pills, capsules, powders, suspensions, solutions, sprays or suppositories, if necessary in combination with other active substances, nab, what antagoniste serotonin, -receptor antagonists, nitrates of Akilov, such as the trinitrate, substances inhibiting phosphodiesterase, prostacyclines and similar substances, anti-fibrinolytic drugs such as tissue plasminogen activator, PUK, streptokinase, or inhibiting clotting medications, such as heparin sulfate, dermatan, activated balkcom C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated clotting factors, together with one or some of the known inert carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, mixture of water and ethanol, a mixture of water and glycerol with a mixture of water and sorbitol, a mixture of water and glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose, cyclodextrins, for example oksipropil-cyclodextrin, or fatty substances, for example utverzhdennym fat, or their suitable mixtures.

The new compounds of General formula I get the following known methods.

P R I m e R 1. (3R,5S)-3-Allyl-5-[(4-zianv paraffin oil) in 1 ml of dry dimethylformamide added 3.7 g (3R,5S)-3-allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl] -2-pyrrolidinone in 20 ml of dry dimethylformamide. Stir at room temperature for one hour, then add 2.1 g of methyliodide in 3 ml of dry dimethylformamide and continue to stir at room temperature for 18 hours Diluted with ice water and complex ethyl ester acetic acid, the organic phase is separated and the water phase extracted twice a complex ester of acetic acid. The combined organic phases are washed with water, dried, filtered and evaporated on a rotary evaporator. The residue is purified by column chromatography on silica gel using as eluent a mixture of cyclohexane and of ester of acetic acid in a volume ratio of 1:1.

Yield: 3.2 g (84% of theory).

The value of Rf: 0,31 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 4:6).

Calculated C 76,28; H 6,40; N 8,08

Found, 75,99; N 6,77; N 7,87

Similarly receive the following connections.

(1) (3R, 5S)-3-Allyl-1-[(aminocarbonyl)methyl] -5-[(4'-cyano-4-biphenylyl)-hydroxy - methyl]-2-pyrrolidinone.

The value of Rf: of 0.60 (silica gel; a complex mixture of ethyl ester of acetic acid and methanol in a volume ratio of 9:1).

Designed WITH 70,93; N 5,95; N 10,79<
The value of Rf: 0,70 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 4:1).

Designed WITH 71,27 N 5,98 N 6,93

Found, 71,19 N 6,18 N FOR 6.81

(3) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-1-[3-(3,4-acid)propyl] -3-[(methoxycarbonyl)methyl]-2-pyrrolidin - non.

The value of Rf: to 0.47 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 4:1).

(4) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-[3- (4-hexyloxyphenyl)propyl]-2-pyrrolidin - non.

The value of Rf: 0.83 (silica gel; complex ethyl ester of acetic acid).

(5) (3S, 5S)-1-[3-(4-Tertbutylphenyl)propyl] -5-[(4'-cyano-4-biphenylyl)oxymethyl]-3 [(methoxycarbonyl)methyl]-2-pyrrolidinone.

The value of Rf: 0,78 (silica gel; complex ethyl ester of acetic acid).

(6) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] -1-[3- (3-triptoreline)propyl]-2-pyrrole - Denon.

The value of Rf: 0,78 (silica gel; complex ethyl ester of acetic acid).

(7) (3S, 5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl] -1-[3-(2,4-dichlorophenyl)-propyl]-3 -[(m

The value of Rf: of 0.71 (silica gel; complex�]-1-[3- (3-benzoylphenyl)propyl]-2-pyrrolidinone.

The value of Rf:0,81 (silica gel; complex ethyl ester of acetic acid).

(9) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-1-(4,4-diphenylbutane)-3-[(methoxy carbonyl)methyl]-2-pyrrolidinone.

The value of Rf: 0,81 (silica gel; complex ethyl ester of acetic acid).

(10) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] 1-[3-(4-methylsulfinylphenyl)propyl]-2 - pyrrolidinone.

The value of Rf: 0,78 (silica gel; complex ethyl ester of acetic acid).

(11) (3S,5S)-1-(4-Biphenylyl)-5-[(4'-cyano-4-biphenylyl)oxymethyl]-3-[(methoxy - carbonyl)methyl]-2-pyrrolidinone.

The value of Rf: 0,81 (silica gel; complex ethyl ester of acetic acid).

(12) (3S, 5S)-3-[(Tertbutyloxycarbonyl)methyl] -5-[(4'-cyano-4-biphenylyl)-hydroxy - methyl]-1-[(pyrrolidin-N-carbonyl)methyl]-2-pyrrolidinone.

The value of Rf: of 0.35 (silica gel; complex ethyl ester of acetic acid).

(13) (3S, 5S)-3-[(Tertbutyloxycarbonyl)methyl] -5-[(4'-cyano-4-biphenylyl)-hydroxy - methyl]-1-[(morpholine-N-carbonyl)methyl]-2-pyrrolidinone.

The value of Rf: of 0.44 (silica gel; complex ethyl ester of acetic acid).

P R I m m e R 2. (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(3-phenylpro - razmeshivaya add a solution of 246 g of (3R,5S)-3-allyl-5-[(methanesulfonate)methyl] -1-(3-phenylpropyl)-2-Pirro - ledenon. Continue to stir at 60aboutC for 20 h, then most of the dimethylformamide evaporated in vacuum. The residue is stirred with 750 ml of complex ethyl ester of acetic acid and 500 ml of water. Phase complex ethyl ester acetic acid, washed with diluted sodium chloride solution, and the aqueous phase again extracted with complex ethyl ester of acetic acid. The organic phases are concentrated and stirred with 1000 ml of simple ether and the seed crystals. The resulting crude product is filtered and washed with simple ether. From the mother solution by chromatography on silica gel (eluent:a mixture of simple ether and concentrated aqueous ammonia in a volume ratio of 10:0,05) further fraction. Raw food is recrystallized from a mixture of methylene chloride and simple ether.

Output: 257 g (85% of theory). So pl. 74-76aboutC.

Similarly receive the following connections.

(1) (3S,5S)-5-[(4'-Benzyloxycarbonylamino)-4-biphenylyl]oxymethyl]-3-[(label - dicarbonyl)methyl]-1-phenyl-2-pyrrolidin - non.

So pl. 157-159aboutC.

The value of Rf: of 0.50 (silica gel, mixture of chloroform and methanol in a volume ratio 95:5)

Designed WITH 71,05 N 5,62 N 7,10

On the 157-159aboutC.

The value of Rf: of 0.37 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 7:3)

Designed WITH 78,91 N 7,99 N 6,13

Found, WITH 79,00 N 8,11 N 5,94

(3) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(4'-methoxybenzyl)-2 - pyrrolidinone.

So pl. 120-122aboutC.

The value of Rf: of 0.56 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 76,97 N 6,24 N IS 6.19

Found, C 76,95 N 6,38 N 6,26

(4) (3S,5R)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(3-phenylpropyl)2-feast - religion.

The value of Rf: of 0.60 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 79,97 of 6.71 N N 6,22

Found, 80,10 N 7,00 N 6,00

(5) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-2-pyrrolidinone.

So pl. 99-101aboutC.

The value of Rf: of 0.38 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:4).

Calculated C 75,88 H 6,06 N 8,43

Found, 75,86 N 6,26 N 8-36

(6) (3R,5S)-3-Allyl-5-{[4-|4'-cyanophenyl|aminocarbonyl)phenyl]oxymethyl} -1- (3-phenylpropyl)-2-pyrrolin the P CLASS="ptx2">

(7) (3S,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-2-pyrrolidinone. So pl. 169-171aboutC.

The value of Rf: a 0.27 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio of 8:2).

Designed WITH 75,88 N 6,06 N 8,43

Found, 75,72 N 6,14 N 8,50

(8) (3R, 5S)-3-Allyl-1-[2-(benzyloxy)ethyl] -5-[(4'-cyano-4-biphenylyl)the oxime-til] 2-PI

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 77,23 N 6,48 N 6,00

Found, 76,97 N 6,57 N 5,97

(9) (3S,5R)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-2-pyrrolidinone.

So pl. 99%-101aboutC.

The value of Rf: of 0.42 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:4).

Designed WITH 75,88 N 6,06 N 8,43

Found, 75,75 N 6,09 N 8,17

(10) (3S, 5S)-3-[(Tertbutyloxycarbonyl)methyl] -5-[(4'-cyano-4-biphenylyl)-oxymethyl-2-

As the Foundation of the use of tributylin potassium.

So pl. 158-159aboutWITH

The value of Rf: of 0.50 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 1:9).

Designed WITH 70,91 N 6,45 N 6,89

the s Rf: of 0.44 (silica gel; a mixture of cyclohexane and complex etilovogo ester of acetic acid in a volume ratio 1:1).

(12) (3R,S;4R,S)-3-Allyl-4-[(4'-Cyano-4-biphenylyl)oxymethyl]-1-(4-methoxybenzyl)- -2-pyrrolidinone.

The value of Rf: 0,22 (silica gel; a mixture of cyclohexane and Slonova ethyl ester of acetic acid in a volume ratio of 2:1).

Designed WITH 76,97 N 6,24 N IS 6.19

Found, WITH 77,10 N 6,47 N 5,98

(13) (3S,5S)-5-{[4'-(N-Benzyloxycarbonylamino)-4-biphenylyl]oxymethyl} -3- [(tertbutyloxycarbonyl)methyl]-2-pyrrole - Denon.

So pl. 136-140aboutC.

The value of Rf: to 0.39 (silica gel; complex ethyl ester of acetic acid.

(14) (3S,5S)-5-{[4-(N-Benzyloxycarbonylamino)-4-biphenylyl]oxymethyl} -3- [(methoxycarbonyl)methyl]-2-pyrrolidinone.

So pl. 160-164aboutC.

The value of Rf: of 0.43 (silica gel; complex ethyl ester of acetic acid).

Calculated C 67,56 H 5,67 N 8,15

Found, 67,31 N 5,63 N 8,09

(15) (3S, 5S)-5-[(7-Cyano-9,10-dihydro-2-phenanthrene)oxymethyl] -3-[(meloxicam - nil)methyl]-2-pyrrolidinone.

The value of Rf: of 0.52 (silica gel; a mixture of methylene chloride, methanol and concetrating aqueous ammonia in a volume ratio of 30:1:0,1).

(THE Rf: of 0.32 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

P R I m e R 3. (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

To of 3.9 g of 4-cyano-4'-oxibutinina in 30 ml of dry dimethylformamide gobalet of 9.8 g of cesium carbonate and intensively stirred at room temperature for 2 hours Then add 7,03 g (3R,5S)-3-allyl-5-[(methanesulfonate)methyl] -1-(3-phenyl - propyl)-2-pyrrolidinone in 20 ml of dimethylformamide and stirred at 55-60aboutC for 18 hours Then cooled, poured into 200 ml of water and shaken out three times ester of acetic acid, the combined organic phases are washed with water, dried over sodium sulfate and concentrated. Purify by chromatography on filled with silica gel column, using as eluent a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 1:1, resulting in a gain of 6.9 g (76% of theory) of the target product.

So pl. 74-76aboutC.

The value of Rf: to 0.47 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Similarly receive the following connections.

Designed With 68,05 N 5,52 N Of 5.29 Br 15,09

Found, 68,18 N 5,61 N 5,34 Br 15,38

(2) (3R,5S)-3-Allyl-5-[(4'-cyano-3-nitro-4-biphenylyl)oxymethyl]-1-(3-phenylpropyl ) -2-pyrrolidinone.

The value of Rf: of 0.54 (silica gel; a mixture of 1,2-dichloroethane and complex ethyl ester of acetic acid in a volume ratio of 3:1).

Designed With 72,71 H 5,90 N 8,48

Found, 72,45 N 5,79 N 8,24

(3) (3R,5S)-3-Allyl-5-[(4'-cyano-3-trifluoromethyl-4-biphenylyl)oxymethyl] -1-(3-Fe - ylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.49 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 71,80; N 5,64 N 5,40

Found, WITH 71,51 N 5,79 N 5,06

(4) (3R,5S)-3-Allyl-5-[(4'-cyano-3-fluoro-4-biphenylyl)oxymethyl]-1-(3-phenylpropyl) -2-pyrrolidinone.

The value of Rf: of 0.51 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 76,90 N 60,24 N 5,98

Found, With 77,10 H 6,59 N 5,94

(5) (3R,5S)-3-Allyl-5-[(4'-cyano-2,3-dimethyl-4-biphenylyl)oxymethyl]-1-(3-phenyl - propyl)-2-pyrrolidinone.

The value of Rf: of 0.56 (silica gel; mixture C 80,30 N 7,16 N 5,85

Found, WITH 79,98 N 7,32 N 5,59

(6) (3S,5S)-5-[(4'-Cyano-2'-methyl-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)IU - Tyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Calculated C 74,97 N 6,50 N 5,64

Found, WITH 74,70 N 6,51 N 5,64

(7) (3R, 5S)-3-Allyl-5-{[4-(4-|tertbutyloxycarbonyl|butyl)phenyl] oxymethyl} 1-(4

The value of Rf: of 0.58 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

(8) (3R,5S)-3-Allyl-5-[(6-cyano-2-naphthyl)oxymethyl]-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: of 0.55 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

(9) (3R,5S)-3-Allyl-5-{[4-(4-|tertbutyloxycarbonyl|butyl)phenyl]-oxymethyl} -1-[

The melting point 79-83aboutC.

The value of Rf: of 0.35 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in the volume ratio 2:1).

(10) (3R, 5S)-3-Allyl-5-{[4-(4-|tertbutyloxycarbonyl|butyl)phenyl] lxine - Teal}-1-[2-(1-naphthyl)ethyl]-2-pyrrolidinone.

The value of Rf: of 0.43 (silica gel; a mixture of the l-1-benzyl-5-{[4-(4-|tertbutyloxycarbonyl|butyl)Fe - Neil]oxymethyl}-2-pyrrolidinone.

The value of Rf: of 0.35 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(12) (3R,5S)-3-Allyl-5-{[4-(4-|tertbutyloxycarbonyl|butyl)phenyl] the oxime - Tyl}-1-(4-phenoxybutyl)-2-pyrrolidinone.

The value of Rf: 0,86 (silica gel; complex ethyl ester of acetic acid).

(13) (3R,5S)-3-Allyl-5-{[4-(4-|4-tertbutyloxycarbonyl|butyl)phenyl] oxymethyl-1-

The value of Rf: of 0.26 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(14) (3R,5S)-3-Allyl-5-{[4-(3-|benzyloxycarbonylamino|propyl)phenyl]the oxime - Tyl}-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.54 (silica gel; a mixture of simple tertbutylamine ether and petroleum ether in a volume ratio 4:1).

(15) (3R,5S)-3-Allyl-5-{[4-(|tertbutyloxycarbonyl|methyl)phenyl]oxymethyl} -1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 20:1).

(16) (3R,5S)-3-Allyl-5-{[3-(|tertbutyloxycarbonyl|methyl)phenyl]oxymethyl} -1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,34 (silica gel; a mixture of methylene chloride is l] oxymethyl} 1-(3

The value of Rf: to 0.45 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 20:1).

(18) (3R, 5S)-3-Allyl-5-{[3-(2-|tertbutyloxycarbonyl|ethyl)phenyl] the oxime-Teal} 1-(3

The value of Rf: to 0.39 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 20:1).

(19) (3R, 5S)-3-Allyl-5-{[4-(2-|tertbutyloxycarbonyl|ethyl)phenyl] the oxime - Tyl}-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 50:1).

(20) (3R, 5S)-3-Allyl-5-{[4-(2-|tertbutyloxycarbonyl|ethyl)phenyl] the oxime-Teal} 1-from

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 20:1).

(21) (3R,5S)-3-Allyl-5-{[4-(CIS-4-|tertbutyloxycarbonyl|cyclohexyl)Fe - Neil]oxymethyl}-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: 0,77 (silica gel; a mixture of methylene chloride and methanol in a volume ratio 9:1).

(22) (3R,5S)-3-Allyl-5-{[4-(TRANS-4-|tertbutyloxycarbonyl|cyclohexyl)Fe - Neil]oxymethyl}-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: 0,79 (silica gel; a mixture of methylene chloride and methanol in a volume ratio 9:1).

(23) (3R,5S)-3-Allyl-5-[(4'-cyano-4-bi the aqueous ethyl ester of acetic acid in a volume ratio of 2:1).

(24) (3R,5S)-3-Allyl-1-benzyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-2-pyrrolidinone.

The value of Rf: 0,41 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(25) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(2-phenylethyl)-2-Pirro - ledenon.

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(26) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(4-phenylbutyl)-2-Pirro, ledenon.

The value of Rf: of 0.35 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(27) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(4-phenoxybutyl)-2-p erro

The value of Rf: of 0.38 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(28) (3R,5S)-3-Allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1,3-bis-(3-phenylpropyl)- 2-PI

The value of Rf: of 0.60 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(29) (3R,5S)-3-Allyl-3-(n-butyl)-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(3-phenyl - propyl)-2-pyrrolidinone.

nom ratio 2:1).

(30) (3R,5S)-3-Allyl-5-{[4-(3-cyanopropyl)phenyl]oxymethyl}-3-methyl-1-(3-phenyl - propyl)-2-pyrrolidinone.

The value of Rf: of 0.36 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(31) (3R,5S)-3-Allyl-5-{[4-(3-cyanopropyl)phenyl]oxymethyl}-1-(3-phenylpropyl)- 2-pyrrolidinone.

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(32) (3R,5S)-3-Allyl-1-[3-(4-benzyloxyphenyl)propyl]-5-{[4-(4-|tertbutoxide-b nilradical.

The value of Rf: of 0.55 (silica gel; a mixture of toluene and acetone in a volume ratio of 2:1).

(33) (3R, 5S)-3-Allyl-5-[(2-cyano-5-indanyl)oxymethyl] -1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: of 0.32 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(34) (3S,5S)-5-[(7-Cyano-9-keto-2-fluorenyl)oxymethyl]-3-[(methoxycarbonyl)methyl] 1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.55 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 1:1). After two chromatography.

(35) (3S,5S)-3-Allyl-5-[(4'-cyano-4-bi is

The value of Rf: of 0.55 (silica gel; simple mixture of ether and concentrated aqueous ammonia in a volume ratio of 10:0,1).

(36) (3R,5S)-3-Allyl-5-{[3-(3-|tertbutyloxycarbonyl|propyl)phenyl] oxymethyl}-1-(3-phenylpropyl)-2-pyrrole - Denon.

The value of Rf: of 0.36 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(37) (3R,5S)-3-Allyl-5-{[4-(5-|tertbutyloxycarbonyl|pentyl)phenyl] -hydroxy - methyl}-3-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(38) (3R,S;5R,S)-3-Allyl-5-{[4-(|tertbutyloxycarbonyl|methyl)phenyl] -hydroxy - methyl}-3-methyl-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.44 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(39) (3R,S;5R,S)-3-Allyl-5-{[4-(2-|tertbutyloxycarbonyl| ethyl)phenyl]oxy - methyl}-3-methyl-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(40) (3R, S; 5R, S)-3-Allyl-5-{ [4-(4-| tert isf: of 0.35 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(41) (3R,5S)-3-Allyl-5-{[4-(|4-cyanophenyl|carbylamine)phenyl]oxymethyl} -1- (3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.63 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio of 3:1).

(42) (3R,5S)-3-Allyl-5-{[4-(|4-cyanophenyl|aminosulfonyl)phenyl]oxymethyl}-1-(3-Fe of nilp

The value of Rf: 0.84 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 4:1).

(43) (3S, 5S)-5-{ [4-(| 3-Cyanophenyl| sulfa - nil)phenyl]oxymethyl}-3-[(methoxycarbonyl) methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.53 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 1:1).

(44) (3S, 5S)-5-{ [4-(| 3-Cyanophenyl| carbonyl)phenyl] oxymethyl} -3-[(meloxicam - nil) methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.36 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 1:1).

(45) (3R,5S)-3-[4-(tertbutyloxycarbonyl)butyl]-5-{[4'-(|methoxycarbonyl| methyl)-4-biphenylyl]oximeter ester of acetic acid in a volume ratio 1:4).

(46) (3S, 5S)-5-{ [4-(CIS-4-|tertbutyloxycarbonyl|cyclohexyl)-phenyl] oxymethyl}-3-[(methoxycarbonyl)methyl]-1- (3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.45 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

(47) (3S,5S)-5-{[4-(TRANS-4-|tertbutyloxycarbonyl|cyclohexyl)-phenyl] oxymethyl} -3-[(methoxycarbonyl)methyl] 1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.45 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

(48) (3S, 5S)-5-[(4'-Cyano-3-methylsulfanyl-4-biphenylyl)oxymethyl]-3-[(methoxy - carbonyl)methyl]-1-(3-phenylpropyl)-2-PI - religion.

The value of Rf: 0,75 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 15:1).

(49) (3R,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)propyl]-1-(3 phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.40 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 19:1).

(50) (3R,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[5-(methoxycarbonyl)-pen - Tyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,33 (silica gel; simple mixture of ether and par-4-biphenyl - yl) oxymethyl]-2-pyrrolidinone.

The melting point of 142-144aboutC.

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride and complex ethyl ester of acetic acid in a volume ratio of 8:2).

Designed WITH 67,91 N 5,94 N 6,60

Found, 67,79 N 5,94 N 6,64

(52) (3S,5S)-3-[(tertbutyloxycarbonyl)methyl]-5-[(3'-chloro-4'-cyano-4-biphenylyl) oxymethyl]-2-pyrrolidinone.

The melting point 140-142aboutC.

The value of Rf: of 0.36 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 3:7).

Calculated, compared with 65.38 N 5,72 N 6,35 Cl 8,04

Found, 65,32 N 5,75 N 6,41 Cl 8,11

(53) (3S,5S)-5-[(3-Bromo-4'-cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)IU - Tyl]-2-pyrrolidinone.

The value of Rf: of 0.52 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 15:1).

Designed With 56,90 N 4,32 N 6,32 Br 18,03

Found, C, 56.78 has to 4.41 H N 6,17 Br 17,92

P R I m e R 4. (3R,S;5S,R)-3-Allyl-5-{4-[(4-cyanomethyl)oxy]phenyl}-1-(3-phenylpro - saws)-2-pyrrolidinone.

A mixture of 3.6 g of (3R,S;5S,R)-3-allyl-5-(4 oksifenil)-1-(3-phenylpropyl)-2-pyrrolidinone, 1.8 g of the nitrile 5-bombalurina acid, 7.6 g of potassium carbonate and 100 ml of acetone is heated under reflux for 24 hours After cooling is filtered and the filter is the PMC using chloroform as eluent.

Yield: 3.9 g (88,3% of theory).

The value of Rf: to 0.10 (silica gel; chloroform).

Designed WITH 77,85 N 7,74 N OF 6.73

Found, WITH 77,56 N 7,84 N 6,66

P R I m e R 5. (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)- methyl]1-(3-phenylpropyl)-2-pyrrolidinone.

To a mixture of 203 g of (3R,5S)-3-allyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]-1-(3-phenylpro - saws)-2-pyrrolidinone, 1800 ml of methylene chloride, 1800 ml of acetonitrile and 2 g of three-hydrate ruthenium at 25-31aboutC for 1.75 h under vigorous stirring drops add a solution of 580 g metaperiodate sodium in 3200 ml of water. Continue to stir for 4 h, and then add again 1800 ml of methylene chloride. The organic phase is separated and washed first with 1000 ml of water, and then 1000 ml of 10% aqueous solution of disulfit natra, in the end again 1000 ml of water. The aqueous phase is extracted twice more, each time using 350 ml of methylene chloride. The combined methylene chloride phase is dried over magnesium sulfate, treated with active charcoal and concentrated. Foamy residue, which represents the (3S,5S)-3-carboxymethyl-5-[(4' - cyano-4-biphenylyl)oxymethyl]-1-(3-phenyl - propyl)-2-pyrrolidinone, use this form.

Output: 208 g (84% of theory).

The value of Rf: 0,66 (silica gel, mixture methylenecholesterol in 1200 ml of methanol, add 10 ml of saturated methanolic hydrochloric acid, stirred at room temperature for 16 h, concentrated and the residue purified by chromatography on silica gel (eluent: a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 1.5:1). Eluent evaporated, the resulting oil product was stirred with 750 ml of simple ether and the seed crystals. The resulting crystallized filtered and washed twice, each time using 150 ml of a simple ester. From mother solutions are further fraction.

Output: 147 g (67% of theory from both stages).

The melting point, 75-76aboutC.

Similarly receive the following connections.

(1) (3S, 5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl] -1-(3-cyclohexylprop)-3- [(methoxycarbonyl)methyl]-2-pyrrolidinone.

The value of Rf: 0,59 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 4:6).

Designed WITH 73,74 N 7,43 N 5,73

Found, WITH 73,52 N 7,60 N 5,46

(2) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-2 - pyrrolidinone.

The melting point 140-142aboutC.

The value of Rf: of 0.42 (silica gel; a mixture of methylene chloride and 3) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-me - til-

The value of Rf: 0,41 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 100:2).

Designed, 69,83 N 5,86 N 7,40

Found, WITH 69,60 N 6,10 N 7,20

(4) (3S,5S)-5-[(3-Bromo-4'-cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl 1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.62 (silica gel; a mixture of methylene chloride and complex ethyl ester of acetic acid in a volume ratio 4:1).

Designed WITH 64,17 N TO 5.21 N 4,99

Found, 64,20 N 5,43 N 5,06

(5) (3S,5S)-5-[(4'-Cyano-3-nitro-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)IU-t Il]

The value of Rf: of 0.53 (silica gel; a mixture of 1,2-dichloroethane and complex ethyl ester of acetic acid in a volume ratio of 3:1).

Designed WITH 68,30 N 5,54 N 7,97

Found, 68,28 H 5,34 N 7,75

(6) (3R,5R)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-(3 - FeNi

The value of Rf: 0,70 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 2:3).

Calculated C 74,66 N 6,27 N 5,81

Found, 74,51 N 6,47 N 5,63

(7) (3S, 5S)-5-[(4'-Cyano-3-trifluoromethyl-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(3-phenylpropyl)-2-pyrrolidin - non.

The value of Rf: to 0.45 (silica gel; the mixture College N 5,09

Found, 67,73 N 5,48 N 5,08

(8) (3S,5S)-5-[(4'-Cyano-3-fluoro-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)IU - Tyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,34 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

(9) (3S, 5S)-5-[(4'-Cyano-2,3-dimethyl-4-biphenylyl)oxymethyl] -3-[(methoxycarbonyl) methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel, mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 4:1).

Designed, 75, 27 H OF 6.71 N 5,49

Found, 74,96 N 7,00 N lower than the 5.37

(10) Semihydrate (3S,5S)-5-{[TRANS-4-(4-cyanophenyl)cyclohexyl]oxymethyl} -3-[(IU - oxycarbonyl)methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.52 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:1).

Designed WITH 72,41 N 7,50 N 5,63

Found, 72,35 to 7.61 N N 5,62

(11) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-3-me - Teal-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,74 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 15:1).

(12) (3S,5S)-1-Benzyl-5-[(4'-cyano-4-biphenylyl)oxymethyl]- ratio 15:1).

(13) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-(2 - phenylethyl)-2-pyrrolidinone.

The value of Rf: of 0.44 (silica gel; a mixture of cyclohexane, complex ethyl ester of acetic acid and methanol in a volume ratio of 64:32:4).

(14) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] -1-(4 - phenylbutyl)-2-pyrrolidinone.

The value of Rf: 0,41 (silica gel; a mixture of cyclohexane, complex ethyl ester of acetic acid and methanol in a volume ratio of 64:32:4).

(15) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-(4 - FeNi

The value of Rf: 0,41 (silica gel; a mixture of cyclohexane, complex ethyl ester of acetic acid and methanol in a volume ratio of 64:32:4).

(16) (3S,5S-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1,3 - bis-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,41 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(17) (3S, 5S)-3-(n-Butyl)-5-[(4'-cyano-4-biphenylyl)oxymethyl] -3-[(methoxycarbonyl) METI

The value of Rf: of 0.42 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio of 2:1).

(19) (3S, 5S)-5-{ [4-(|4-Cyanophenyl|carbylamine)phenyl]oxymethyl}-3-[(methoxy - CT - bonyl)methyl]-1-(3-phenylpropyl)-2-pyrrole - Denon.

The value of Rf: of 0.35 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 1:1).

(20) (3S, 5S)-5-{[4-(|4-Cyanophenyl|aminosulfonyl)phenyl]oxymethyl}-3-[(label-Sikar Boni)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: to 0.28 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio of 3:1).

(21) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] -3-me - til-2-pyrrolidinone.

The melting point of 105-107,5aboutC.

The value of Rf: a 0.27 (silica gel; a mixture of cyclohexane and complex ethyl ester of acetic acid in a volume ratio 1:4).

Designed WITH 69,83 N 5,86 N 7,40

Found, 69,64 N 5,73 N 7,70

(22) (3S,5S)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] -1- (2-methoxyethyl)-2-pyrrolidinone.

The value of Rf: of 0.55 (silica gel; a mixture of toluene, dioxane, ethanol and glacial acetic acid in a volume ratio 90 10 10 6).

Calculated C and - CT - bonyl)methyl]-2-pyrrolidinone.

The value of Rf: of 0.26 (silica gel; complex ethyl ester of acetic acid).

(24) (3R,5R)-5-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)-methyl] -2-pyrrolidone.

The melting point of 138-140aboutC.

The value of Rf: of 0.51 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 100:2).

Designed WITH 69,22 N OF 5.53 N 7,69

Found, C 68,98 H 5,51 N 7,62

(25) (3R,S;4R,S)-4-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] -2-pyrrolidinone.

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 98:2).

(26) (3R, S; 4R, S)-4-{[(4'-Cyano-4-biphenylyl)carbylamine]methyl}-3-[(meloxicam - bonyl)methyl]-2-pyrrolidinone.

The value of Rf: of 0.16 (silica gel; a complex mixture of ethyl ester of acetic acid and methanol in a volume ratio of 97:3).

(27) (3R,S;4R,S)-4-[(4'-Cyano-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl] 3-methyl-2-pyrrolidinone.

The melting point of 163-164aboutC.

The value of Rf: to 0.39 (silica gel; complex ethyl ester of acetic acid).

Calculated C 69,82 H 5,86 N 7,40

Found 70,00 N 6,10 N 7,55

P R I m e R 6. Semihydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)-oxime - Tyl]-3-[(IU shall oxycarbonyl)methyl] -1-(3-Fe - ylpropyl)-2-pyrrolidinone (140 g), dissolved in 1100 ml of methanol and cooled to -20aboutC. At this temperature for 4 h under stirring injected gaseous hydrochloric acid, and continue to stir at room temperature for 16 hours the Solvent is evaporated in vacuo, resulting in a gain of 172 g of the crude hydrochloride complex aminoether in the form of a viscous oil. This crude product is dissolved in 1500 ml of methanol, added 144 g of ammonium carbonate and stirred at room temperature for 2 hours Then add another 48 g of ammonium carbonate and stirred for 1.5 hours, the Reaction mixture by addition of methanolic hydrochloric acid with stirring to bring the pH to 3.5. In vacuum concentrated to approximately 800 ml and usageprice ammonium chloride is filtered off. The filtrate is further concentrated to the beginning of crystallization, i.e., approximately 350 ml At the end of the crystallization of the precipitate is filtered off and washed with 75 ml of ice-cold methanol and then with acetone and simple ether. In the thickening of the filter residues are further fraction. Both kristalliset are combined and recrystallized from methanol.

Output 128,7 g (83% of theory).

The melting point 184-187aboutC (decomposition).

Designed With 66,11 N 6,47 N 7,71 CL 6,50
orig (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(3-cyclohexyl - ropyl)-3-[(methoxycarbonyl)methyl]-2-feast-of religion.

The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(2) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)-methyl] -2-pyrrolidinone x 1.25 Hcl.

Melting point ranging from 141aboutC (decomposition).

The value of Rf: to 0.30 (silica gel, mixture of methylene chloride and methanol in a volume ratio 85:15).

Designed With 59,07 N 5,72 N 9,84 Cl 10,38

Found, 58,96 N 5,96 N 9,68 Cl 10,10

(3) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(methoxycarbonyl) methyl]-1-methyl-2-pyrrolidinone.

Melting point ranging from 138aboutC (decomposition).

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(4) Hydrochloride (3S,5S)-5-[(4'-amidino-3-bromo-4-biphenylyl)oxymethyl]-3-[(label-dicarbonyl)IU Teal]pyrrolidinone.

The melting point of 104-106aboutC (decomposition).

The value of Rf: 0,46 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 40 10 2).

Designed WITH 58,59 N 5,41 N 6,83

Found, 58,70 N 5,66 N 6,64

(5) Hydrochloride (3S,tx2">

The value of Rf: to 0.63 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(6) Semihydrate (3R,5R)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(methoxy-carbonyl)methyl]-1- (3-froh - ledenon.

The value of Rf: of 0.43 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

Designed With 69,58 N 6,52 N 8,11 Cl 3,42

Found, C 69,69; H 6.73 x N 7,97 Cl 2,86

(7) Hydrochloride (3S, 5S)-5-[(4'-amidino-3-trifluoromethyl-4-biphenylyl)oxymethyl]-3- [(methoxycarbonyl)methyl]-1-(3-phenylpropyl) -2-pyrrolidinone.

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(8) Hydrochloride (3S,5S)-5-[(4'-amidino-3-fluoro-4-biphenylyl)oxymethyl]-3-[(methoxy - carbonyl)methyl]-1-(3-phenylpropyl)-2-PI - religion.

The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(9) Hydrochloride (3S,5S)-5-[(4'-amidino-2,3-dimethyl-4-biphenylyl)oxymethyl]-3-[(IU - oxycarbonyl)methyl]-1-(3-phenylpropyl)- 2-pyrrolidinone.

The value of Rf: 0,42 (silicagel

(10) Hydrochloride (3S, 5S)-5-[(3-acetylamino-4'-amidino-4-biphenylyl)oxymethyl] -3-[(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(11) Hydrochloride (3S,5S)-5-[(4'-amidino-3-methanesulfonamido-4-biphenylyl)OK-simetal]-3-[(meth oxiranylmethyl)-2-pyrrolidinone.

The value of Rf: of 0.42 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(12) Hydrochloride (3S,5S)-5-[(4'-amidino-2'-methyl-4-biphenylyl)oxymethyl] -3-[(method xianbei)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.44 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(13) Hydrochloride (3S,5S)-5-{[(4'-amidino-4-biphenylyl)carbonyl]aminomethyl}-3- [(methoxycarbonyl)methyl]-1-(3-phenylpropyl)- 2-pyrrolidinone.

The value of Rf: 0,34 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 40 10 2).

(14) Hydrochloride (3S,5S)-5{[TRANS-4-(4-amidinophenoxy)cyclohexyl]oxymethyl}-3- [(meloxicam is a, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

(15) Hydrochloride (3S,5S)-5-{2-[(6-amidino-2-afterburner)amino]ethyl} -3-[(method xianbei)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.26 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 3).

(16) Hydrochloride (3S,5S)-5-[(6-amidino-2-afterburner)aminomethyl]-3-[(label-dicarbonyl)METI l]-pyrrolidinone.

The value of Rf: of 0.26 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 3).

(17) Hydrochloride (3S,5S)-5-[(7-amidino-2-afterburner)aminomethyl]-3-[(methoxy - carbonyl)methyl]-1-(3-phenylpropyl)-2-PI - religion.

The value of Rf: to 0.19 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 9 to 1).

(18) Hydrochloride (3S,5S)-5-{2-[(7-amidino-2-afterburner)amino]ethyl} -3-[(IU - oxycarbonyl)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 9 to 1).

(19) Hydrochloride (3S,5S)-5-{[TRANS-3-(4-amidinophenoxy)cyclobutyl]carbonyl-AMI - nametil]-3-[(methoxycarbonyl)IU is chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

Calculated C 61,31 H 7,10 N 9,86

Found, 61,45 N 7,18 N FOR 9.64

(20) Hydrochloride (3S,5S)-5-{[CIS-3-(4-amidinophenoxy)cyclobutyl]carbylamine - methyl]-3-[(methoxycarbonyl)methyl-1-(3-Fe - ylpropyl)-2-pyrrolidinone x 1.5 H2O.

The value of Rf: of 0.42 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

Calculated C 61,31 H 7,10 N 9,86

Found, C 61,67 H 6,98 N 9,80

(21) Hydrochloride (3S,5S)-5-{2-[(CIS-3-|4-lidinopril|cyclobutyl)CARBONYLS-but]ethyl]-3-[(meth oxiranylmethyl)-2-pyrrolidinone.

The value of Rf: to 0.48 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

(22) Hydrochloride (3S, 5S)-5-{ 2-[(TRANS-3-| 4-lidinopril| cyclobutyl)carbonyl-Mino]ethyl}-3-[(m etok(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.48 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

(23) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(aminocarbonyl) methyl]-1-(3-phenylpropyl)-2-pyrrolidino. Complex iminoethyl together with metangula (eluent: a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

The value of Rf: of 0.35 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(24) Hydrochloride, (3R,5S)-3-allyl-5-{[3-(3-amidinophenoxy)propyl]carbonylmethyl} -1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.30 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 4 to 1 by 0.1).

(25) Hydrochloride (3S,5S)-5-{[3-(4-amidinophenoxy)propyl]carbonylmethyl}-3- [(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 4 to 1).

(26) Hydrochloride (3S, 5S)-5-[(4-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-3-methyl-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2),

(27) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-benzyl-3-[(method xianbei)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: to 0.19 (silica gel; the mix CLASS="ptx2">

(28) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(2-phenylethyl)-2-pyrrolidinone.

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(29) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(4-phenylbutyl)-2-pyrrolidin Nona.

The value of Rf: 0,41 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(30) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(4-phenoxybutyl)-2-Pirro - ledenon.

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(31) Hydrochloride (3S,5S)-5-{[4'-(n-butylamino)-4-biphenylyl]oxymethyl} -3-[(method xianbei) methypyridine. Complex iminoethyl absorb in absolute methanol and to the solution add 20-fold molar amount of n-butylamine.

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated in the (3S,5S)-5-{[4'-(n-butylamino)-4-biphenylyl] oxymethyl]-3-[(n-butyl - noncarbonyl)methyl]-1-(3-phenylpropyl)-2 - pyrrolidinone.

The value of Rf: of 0.60 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 4 to 1 by 0.2).

(32) Hydrochloride (3S,5S)-3-[(methoxycarbonyl)methyl]-5-[(4'-methylamino-4-bi - fenril)oxymethyl] -1-(3-phenylpropyl)-2-pyrrolidinone. The interaction is carried out analogously to example 6 (31).

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

As a by-product receive hydrochloride (3S,5S)-5-[(4'-methylamino-4-biphenylyl)oxymethyl[-3-[(methylamino - carbonyl)methyl]-1-(3-phenylpropyl)-2-feast - of religion.

Designed With 67,80 N 6,79 N 10,20 Cl 6,46

Found, 67,35 N 6,68 N 10,23 Cl to 6.43

(33) Hydrochloride (3S,5S)-5-[(4'-isopropylamino-4-biphenylyl)oxymethyl] -3-[(IU - oxycarbonyl)methyl] -1-(3-phenylpropyl)-2-pyrrolidinone. The interaction is carried out analogously to example 6 (31).

The value of Rf: to 0.47 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(34) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1,3-bis-(3-phenylpropyl)-2-PI - rolidone the data of aqueous ammonia in a volume ratio 68 15 15 2).

(35) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-(n-butyl)-3-[(IU-oxycarbon Il)m

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(36) Hydrochloride, (3R,5S)-3-allyl-5-[(4'-amidino-4-biphenylyl)oxymethyl] -1-(3-Fe - ylpropyl)-2-pyrrolidinone.

Melting point ranging from 100aboutWith sintering.

The value of Rf: of 0.26 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 8 1 0,25).

(37) Hydrochloride, (3R,5S)-3-allyl-5-[(6-amidino-2-naphthyl)oxymethyl]-1-(3-phenyl - propyl)-2-pyrrolidinone.

The value of Rf: a 0.27 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(38) Hydrate hydrochloride (3S, 5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-[(methoxycarbonyl)METI l]-pil)-2-pyrrolidinone.

Designed With 64,13 N 5,69 N 7,24 Cl 6,12

Found, With 64,90 N 5,86 N 7,39 Cl 6,76

(39) Hydrochloride, (3R, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(3-phenylpropyl)-2-pyrrolidin Nona.

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride, methanolic)aminomethyl]-3-[(methoxycarbonyl)-methyl] -1-(3-phenylpropyl)-2-pyrrolidinone x 1.25 HCl.

Designed With 66,15 N 6,48 N 10,29 Cl 8,15

Found, 65,96 N 6,66 N 10,38 Cl of 7.96

(41) Hydrochloride (3S,5S)-5-{[N-(4'-amidino-4-biphenylyl)-N-methanesulfonyl] AMI - but - methyl}-3-[(methoxycarbonyl)methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

Designed With 60,62 H 6.25 N 9,12 Cl 5,77

Found, in comparison with 60.87 N 6,14 N 8,93 Cl 5,66

(42) Hydrochloride (3S,5S)-5-{[N-(4'-amidino-4-biphenylyl)-N-acetyl]aminomethyl} -3- [(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

Designed With 66,59 N 6,47 N 9,71 Cl 6,14

Found, 66,61 N 6.85 N 9,52 Cl 5,94

(43) Hydrochloride (3S,5S)-5-{[2-(|4-lidinopril|amino)phenyl]carbylamine-methyl} -3-[(methoxy arbor)methyl]-1-(3-Fe - Nile - propyl)-2-pyrrolidinone.

Melting point ranging from 105aboutC (decomposition).

The value of Rf: a 0.27 (silica gel; a mixture of cyclohexane, complex ethyl ester of acetic acid and methanol in a volume ratio 2 1 0,6).

(44) Hydrochloride (3S,5S)-5-{[4-(|4-lidinopril|aminocarbonyl)phenyl]the oxime - Tyl} -3-[(methoxycarbonyl)methyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.63 (silica gel; a mixture of methylene chloride and ethanol in a volume ratio of 4 to 1).

Mass spectrum: (M + N)+543.

(45) Hydrochloride ((3S,5S)-5-{[4-(|4-lidinopril|carbylamine)phenyl] hydroxy - m mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 16 4 1).

(46) Hydrochloride (3S,5S)-5-{[4-(|4-lidinopril|aminosulfonyl)phenyl] xime - Tyl}-3-[(methoxycarbonyl)methyl]-1-(3-phenyl - propyl)-2-pyrrolidinone.

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 16 2 1).

Mass spectrum: (M + N)+579.

(47) Hydrochloride (3S,5S)-5-{[4-(|3-lidinopril|sulfenyl)phenyl]oxymethyl}-3- [(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: of 0.42 (silica gel; a complex mixture of ethyl ester of acetic acid and cyclohexane in a volume ratio 3 2).

(48) Hydrochloride (3S,5S)-5-{[4-(|3-lidinopril|carbonyl)phenyl]oxymethyl}-3-[(methoxycarbonyl )Metel)-2-pyrrolidinone.

The value of Rf: of 0.21 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 16 4 1).

(49) Hydrochloride (3S,5S)-5-{[4-(|3-lidinopril|sulfonyl)phenyl]oxymethyl}-3-[(methoxycarbonyl l)mail)-2-pyrrolidinone.

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride, ethanol and concentrated aqueous ammonia in a volume ratio Lil)oxymethyl]-1,3-bis-[(methoxycarbonyl)METI l]-Winona.

The value of Rf: to 0.40 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 15 5 1).

Designed With 57,77 N 5,86 N 8,42 Cl 7,11

Found, 57,97 N 5,95 scored 8.38 N Cl 7,37

Mass spectrum: (M + N)+454.

(51) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -1-[(ethylamino - bonyl)methyl] -3-[(methoxycarbonyl)methyl] -2-pyrrolidinone x 0,25 H2O.

The value of Rf: a 0.27 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 30 10 2).

Designed With 59,17 N 6,26 N 11,04 Cl 6,99

Found, With $ 59.13 USD N 6,47 N 10,91 Cl 6,78

(52) Semihydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -1-[(di - methylaminomethyl)methyl]-3-[(methoxycarbonyl)methyl] -2-pyrrolidinone.

The Rf-value: 0,33 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 30 10 2).

Calculated C 58,65 H 6,30 N 10,94 Cl 6,92

Found, With 58,50 N 6,55 N 10,79 Cl 6,80

(53) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -1-[(benzylamino - carbonyl)methyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride, methanol and conc is, the 64,06 N 6,00 N 9,92 Cl of 6.31

(54) Semihydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-Ben - zoilus-3-[(methoxycarbonyl)methyl]-pyrrolidine.

The value of Rf: of 0.18 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

Designed With 65,05 N 6.04 N 8,13 Cl 6,86

Found 65,00 H 6,30 N 7,99 Cl 6,61

(55) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-methanesulfonyl-3- [(methoxycarbonyl)methyl]-pyrrolidine.

The value of Rf: to 0.24 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

Calculated C 54,82 N 5,85 N 8,72 CL of 7.36

Found, 54,68 N Of 5.82 N Of 8.47 Cl 7,20

(56) Hydrochloride (3S,5S)-1-acetyl-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3- [(methoxycarbonyl)methyl]-pyrrolidine.

The value of Rf: of 0.16 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

Designed With Of 61.95 N 6,33 N 9,42 Cl of 7.95

Found, 61,76 N Of 6.31 N 9,11 Cl 7,84

(57) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-1-(acylaminoalkyl)-3- [(methoxycarbonyl)methyl]-pyrrolidin x 1.25 HCl.

The value of Rf: of 0.13 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

Designed With 59,58 N 6,51 N 11,58 CL 9,16

Found, 59,73 N 6,56 N 11,33 Cl 9,07

The melting point 196-198aboutC.

The value of Rf: of 0.18 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1). Calculated C 54,06 H 6,11 N 10,96 Cl 6,94 S 6,27 Found, 53,92 N 6,14 N 10,77 Cl 7,02 S 6,32

(59) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(methoxycarbonyl - yl) methyl]-1-methyl-pyrrolidine.

The value of Rf: of 0.18 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

Mass spectrum: (M + H)+382.

(60) Hydrochloride, (3R, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-2-pyrrolidinone.

The value of Rf: of 0.20 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 9 to 1).

Calculated C 57,86 H 6,01 for 9.64 N Cl 8,13

Found, C 58,06 H 5,93 N 9,66 Cl 8,25

(61) Semihydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(IU - oxycarbonyl)methyl]-3-methyl-2-pyrrole - Winona.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 2).

Calculated C 59,93 H 6,17 at 9.53 N Cl 8,04

Found, C 59,79 H between 6.08 N 9,37 Cl 8,21

(62) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-(2-methoxyethyl)-2-pyrroline - n/SUB>: to 0.39 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

(63) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(2-oxyethyl)-3-[(IU - oxycarbonyl)methyl]-2-pyrrolidinone.

As grounds using concentrated aqueous ammonia.

The value of Rf: of 0.55 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4). (3S,5S)-5-[(4'-amidino-4-biphenylyl)OK-simetal]-3-carboxymethyl-1-(2-oxyethyl )-pyrrolidine.

The value of Rf: 0,70 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

(64) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(taxicab - nil)methyl]-2-pyrrolidinone.

As the acid used ethanolic hydrochloric acid.

The value of Rf: of 0.44 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Designed, 60,55 N 6,12 N 9,63 Cl 8,12

Found, C 60,49 H 6,23 N 9,65 Cl 8,21

(65) Semihydrate hydrochloride (3R,5R)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(IU - oxycarbonyl)methyl]-2-pyrrolidinone.

The melting point 138about(Razloga in a volume ratio of 6 to 4).

Calculated C 59,08 H 5,90 N 9,84 Cl 8,31

Found, C 58,96 to 6.19 H N 9,68 Cl 8,93

(66) Hydrochloride (3S,5S)-5-{2-[(4'-amidino-3-biphenylyl)amino]ethyl}-3-[(metaxya - bonil)methyl]-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: to 0.39 (silica gel; a mixture of chloroform and methanol in a volume ratio of 3 to 1).

(67) Hydrochloride (3S,5S)-5-{2-[(|3'-amidino-4-biphenylyl|carbonyl)amino] -ethyl} 3-[(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: to 0.39 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 3 to 1).

(68) Hydrochloride (3S,5S)-5-[(4'-amidino-3-methylsulphonyl-4-biphenylyl)-oxymethyl] -3-[(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: to 0.24 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and aqueous ammonia at a volume ratio of 7 1,5 1,5 0,2).

Mass spectrum: (M + N)+578.

(69) Hydrochloride (3S,5S)-5-[(4'-amidino-3-methylsulfinyl-4-biphenylyl)-oxymethyl] 3-[(methoxycarbonyl)methyl]-1-)3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and aqueous ammonia at a volume ratio of 7 1,5 1,5 0,2). Calculated C 63,96 H 6,23 N 7,22 S 5,51 Cl 6,09 Found, 64,12 N 6,50 N 7,03 S Are 5.36 Cl 5,88

The value of Rf: to 0.19 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio of 7 1,5 1,5 0,2).

(71) Hydrochloride (3S, 5S)-5-{ 2-[(4'-amdinocillin)amino]ethyl}-3-[(meloxicam - bonyl)methyl]-1-(3-phenylpropyl)-2-pyrrole - Winona.

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride, cyclohexane, methanol and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(72) Semihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-[3-(3,4-di - methoxyphenyl)propyl]-3-[(meloxicam - nil)methyl]-2-pyrrolidinone.

The value of Rf: to 0.24 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

Calculated C 66,51 H 6,54 N 7,27 Cl 3,07

Found, C 66,34 of 6.31 H N 7,07 C 2,92

(73) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-[3-(4-hexyloxyphenyl)propyl] 2-pyrrolidinone.

The value of Rf: to 0.23 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(74) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-[3-(4-tertbutyl - phenyl)propyl]-3-[(methoxycarbonyl)methyl] nogo aqueous ammonia in a volume ratio 4 1 0,25).

(75) Hydrochloride (3S, 5S)-5-[(4' -amidino-4-biphenylyl)oxymethyl]-3-[(meloxicam - bonyl)methyl]-1-[3-(3-triptoreline)propyl]-2-pyridinone.

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(76) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-[3-(2,4-dichloro-phenyl)propyl] -3-[2-pyrrolidinone.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(77) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-[3-(3-benzoylphenyl)propyl]-2-pyrrolidinone.

The value of Rf: 0,34 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(78) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(4,4-defenive-Tyl)-3-[(methods of xylidine.

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(79) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-[3-(4-methylsulfinylphenyl)-propyl]-2-pyrrolidyl ammonia in a volume ratio 4 1 0,25).

(80) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-[3-(4-methylsulfinylphenyl) propyl]-2-pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 4 2 of 0.25).

(81) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(4-biphenylyl - Tyl)-3- [(methoxycarbonyl)methyl]-2-pyrrolidinone.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 4 2 of 0.25).

Designed With 69,91 N By 5.87 N 7,19 CL 6,07

Found, 69,82 N 5,86 N 7,39 Cl 6,17

(82) Hydrochloride, (3R,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[3-(meloxicam-bonyl)propyl] -1-(ledenon.

The value of Rf: of 0.51 (silica gel; a mixture of methylene chloride, methanol and water in a volume ratio 8 2 0,10).

Calculated C 68,13 H 6,79 N 7,45

Found, C 67,94 H 7,03 N 7,26

(83) Hydrochloride, (3R,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[5-(meloxicam-bonyl)pentyl] -1-(ledenon.

The value of Rf: of 0.65 (silica gel; a mixture of methylene chloride, methanol and water in a volume ratio 8 2 0,10)

Calculated C 68,96 H 7,15 N 7,10

Found, C 68,82 H 7,22 N 6,97

(84) Hydrochloride (3S,5S)-"ptx2">

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

Mass spectrum: (M + H)+527.

(85) Hydrochloride (3S,5S)-5-{[(4'-amidino-3-biphenylyl)carbonyl]aminomethyl}-3- [(methoxycarbonyl)methyl]-1-(3-phenylpro - saws)-2-pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

Mass spectrum: (M + H)+527.

(86) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)sulfanilyl]-3-[(methoxy - carbonyl)methyl]-1-(3-phenylpropyl)-2-feast - of religion.

The value of Rf: of 0.16 (silica gel; a mixture of methylene chloride, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68 15 15 2).

(87) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)sulfanilyl]-3-[(methoxy - carbonyl)methyl]-1-(3-phenylpropyl)-2-feast - of religion.

The value of Rf: 0,81 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(88) Hydrochloride (3S,5S)-5-{[(1-|4-lidinopril|-1-propen-3-yl]aminocarbonyl] methyl} -3-[(methoxycarbonyl)methyl]-1-(3-Fe - ylpropyl)-2-pyrrolidino ammonia in a volume ratio 4 1 0,25).

(89) Semihydrate hydrochloride (S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3,3-dial - Lil-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

Calculated C 66,27 H 6,72 N 9,66 Cl 8,15

Found, C 66,32 H 6,90 N 9,65 Cl of 7.90

(90) Hydrochloride, (3R,5S)-3-allyl-5-[(4'-amidino-4-biphenylyl)oxymethyl] -2-Pirro - ledenon.

The value of Rf: to 0.68 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 4 to 1).

Calculated C 63,87 H 6,38 at 10.64 N Cl 8,98

(x 0.5 H2O)

Found, C 63,60 H 6,39 N 10,45 Cl 9,25

(91) Hydrochloride, (3R,S;4R,S)-4-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(methoxy-carbonyl)methyl-2-

The value of Rf: to 0.30 (silica gel; a mixture of methylene chloride, methanol and aqueous ammonia at a volume ratio 80 20 5).

(92) (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-(2-oxyethyl)-2-pyrrolidin - non x 1.25 HCl x 1 H2O

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 85 to 15).

Calculated C 57,61 H 6,34 N 10,07 Cl 10,63

Found, C 57,89 H 6,22 N 9,94 Cl 10,46

(93) Hydrochloride (3S, 5S)-5-[(7-amidino-9,10-dihydro-2-phenanthrene)oxymethyl]-3 -[(methoxycarbonyl)methyl]-2-pyrrolidine.

(94) Hydrochloride (3S,5S)-5-[(3'-amidinophenoxy)aminomethyl]-3-[(methoxycarbonyl)methyl]-1-(3-Fe of nilp

The value of Rf: a 0.27 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

Mass spectrum: (M + N)+451.

(95) Hydrochloride (3S,5S)-5-{[Exo-5-(4-amidinophenoxy)Bicycle.2.1| heptyl-Exo-2-carbonyl]aminomethyl}-3-[(meloxicam - bonyl)methyl]-1-(3-phenylpropyl)2-pyrrole - Winona.

The value of Rf: a 0.27 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(96) Semihydrate hydrochloride (3S, 5S)-5-[(4'-amidino-3'-fluoro-biphenylyl)-oxymethyl] 3-[(methoxycarbonyl)methyl]-2-pyrrolidin Nona.

The value of Rf: of 0.56 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 56,70 H 5,43 N 9,45 Cl 7,97

Found, C 56,61 of 5.45 H N 9,49 Cl 8,01

(97) (3S, 5S)-5-{ [4'-(N-benzylamino)-4-biphenylyl] oxymethyl} -3-[(meloxicam - nil)methyl]-2-pyrrolidinone x 1.5 hydrochloride.

The interaction is carried out analogously to example 6 (31).

The melting point 206-208aboutC.

The value of Rf: of 0.44 (silica gel; a mixture of methylene chloride and m
(98) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - nil)methyl]-1-[(4-methoxyphenyl)sulfonyl] 2-pyrrolidine.

The value of Rf: of 0.55 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 9 to 1).

(99) Hydrochloride (3S,5S)-5-[(4'-amidino-3'-chloro-4-biphenylyl)oxymethyl] -3-[(label-dicarbonyl)m ethyl

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride and methanol in a volume ratio 4:1).

Mass spectrum: (M + N)+416 and 418.

(100) Hydrochloride, (3R,S;4R,S)-4-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(methoxy-carbonyl)methyl-3-

The value of Rf: of 0.53 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

(101) Hydrochloride, (3R,S;4R,S)-4-{[(4'-amidino-4-biphenylyl)carbylamine] -methyl}-3-[(meloxicam Boni

The value of Rf: to 0.23 (silica gel; a mixture of methylene chloride, methanol and glacial acetic acid in a volume ratio 80 20 2).

(102) Hydrochloride (3S,5S)-5-[(4'-amidino-3-bromo-4-biphenylyl)oxymethyl] -3-[(IU-oxycarbonyl)IU Teal]

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 1 0,25).

(103) Hydrochloride (3S,5S)-5-[(4'-amide the value of Rf: of 0.42 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 4 to 1).

(104) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - bonyl)methyl]-1-[(pyrrolidin-N-carbonyl)- methyl]-2-pyrrolidinone.

The value of Rf: 0,46 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 30 10 2).

(105) Hydrochloride (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-[(meloxicam - bonyl)methyl]-1-[(morpholine-N-carbonyl)IU - Tyl]-2-pyrrolidinone.

The value of Rf: 0,46 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 30 10 2).

(106) Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-metaxia-Tyl-3-[(metaxya of rondina.

The value of Rf: to 0.10 (silica gel; a mixture of methylene chloride and methanol in a volume ratio of 10 to 1).

(107) 1-(4'-Amidino-4-biphenylyl)-4-phosphonomethyl-2-pyrrolidinone.

The value of Rf: to 0.73 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 1 to 1).

(108) 1-(4'-Amidino-4-biphenylyl)-4-(O-methyl-(phosphonomethyl)-2-pyrrolidinone.

The value of Rf: of 0.55 (silica gel; a mixture of methanol, midine-4-biphenylyl)oxymethyl]-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

Hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl-yl)methyl] -1- (3-f(125,7 g) when heated, dissolved in 1000 ml of methanol. The solution is cooled to 20aboutWith and with stirring, add 355 ml 1 N. sodium lye. After one hour, add 120 ml of 1 N. sodium liquor, and after a further 3 h, 40 ml of 1 N. sodium lye. Continue to stir at room temperature for 16 hours To the reaction mixture add a solution of 32 g of ammonium chloride in 200 ml of water, resulting begins crystallization of the product. After crystallization, the product is filtered, washed twice, each time using a mixture of 4 h of methanol and 1 tsp of water, and then double-digitalout, each time with 250 ml of acetone. The obtained crude product is twice recrystallized from 400 ml of a mixture of methanol, water and concentrated aqueous ammonia in a volume ratio of 40 to 1 to 1.5.

Output 74,7 g (63% of theory).

The melting point of 168aboutC (decomposition).

Calculated C 69,17 H 6,61 N 8,48

Found, C 69,45 H 6,47 N 8,48

From the mother solution obtained by purification of the crude product by evaporation and chromatography on silica gel (eluent: a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volumetric coorelation.

The output of 10.5 g (9% of theory).

The melting point 183-186aboutC.

Similarly receive the following connections.

(1) Dihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-Fe - Neil-2-pyrrolidinone.

Melting point ranging from 215aboutC (decomposition).

The value of Rf: to 0.45 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 65,12 H 6,09 N 8,76

Found, 65,32 N 5,94 N 8,75

(2) Hydrate (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(3-cyclohexylprop)-3-carb oxy

The melting point of 182 to 190aboutC (decomposition).

The value of Rf: 0,13 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Designed WITH 68,34 N 7,71 N 8,24

Found, 68,24 N 7,87 N 8,13

(3) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-2-Pirro-lidine N.

The melting point 292-294aboutC (decomposition).

The value of Rf: 0,63 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C, compared with 65.38 H 5,76 N 11.44

Found, C 65,20 H 5,80 N 11,54

(4) (3S,5S)-5-[(4'-amidino-4-biphenylyl)CLASS="ptx2">

The value of Rf: of 0.20 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

Calculated C 65,36 H 6,14 N 10,89

Found, C 65,32 H 5,97 N 10,84

(5) Hydrate (3S,5S)-5-[(4'-amidino-3-bromo-4-biphenylyl)oxymethyl]-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

The melting point 236-238aboutC (decomposition).

The value of Rf: to 0.45 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 40 40 5). Calculated C 59,80 H 5,54 N 7.21 Br 13,72 Found, C 60,00 H 5.73, N 6,97 Br 13.56MHz

(6) Hydrate (3S,5S)-5-[(4'-amidino-3-nitro-4-biphenylyl)oxymethyl]-3-carboxyl - Teal-1-(3-phenylpropyl)-2-pyrrolidinone.

Melting point ranging from 192aboutC(decomposition), starting with 180aboutWith sintering.

The value of Rf: of 0.18 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 30 5).

Calculated C 63,49 H 5,88 N OF 10.21

Found, C 63,64 H 5,93 N 10,33

(7) Semihydrate (3R,5R)-5-[(4E-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(3-phenylprop yl)-

The melting point of 183-185aboutC (decomposition).

The value of Rf: to 0.23 (silica gel; a mixture of methylene chloride, methanol and the end of the, C 70,82 H IS 6.78 N 8.54

[]D20-39,8; c 1, glacial acetic acid.

(8) Hydrate (3S,5S)-5-[(4'-amidino-3-trifluoromethyl-4-biphenylyl)oxymethyl] -3-carboxyl - Teal-1-(3-phenylpropyl)-2-pyrrolidinone.

The melting point of 238-240aboutC (decomposition).

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 6).

Calculated C 63,00 H 5,64 N 7,35

Found, C 63,16 H 5,98 N 7,37

(9) Hydrate (3S,5S)-5-[(4'-amidino-3-fluoro-4-biphenylyl)oxymethyl]-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

The melting point 195-197aboutC (decomposition).

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

Designed, up 66,78 C H to 6.19 N 8,06

Found, C 66,90 H 6,20 N 8,06

(10) Hydrate (3S,5S)-5-[(4'-amidino-2,3-dimethyl-4-biphenylyl)oxymethyl]-3-Carbo-ximity-1 -(3-

The melting point 211-213aboutC (decomposition).

The value of Rf: of 0.14 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 14 5 1).

Calculated C 70,04 H 7,02 N OF 7.90

Found, C 70,22 H 6,79 N 8,06

(11) Semihydrate hydrochloride">

The melting point of 183-185aboutC (decomposition).

The value of Rf: to 0.17 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 40 10 3).

Calculated C 63,31 H 6,17 N AT 9.53

Found, C 63,59 of 6.31 H N 9,65

(12) (3S,5S)-5-[(4'-amidino-3-methanesulfonamido-4-biphenylyl)oxymethyl] -3-ka - boxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone x 0,25 H2O.

The melting point 219-220aboutC (decomposition).

The value of Rf: to 0.23 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 80 20 5).

Calculated C 61,78 H 5,96 N BEING 9.61

Found, C 61,82 H 6,22 N 9,48

(13) Semihydrate (3S,5S)-5-[(4'-amidino-2'-methyl-4-biphenylyl)oxymethyl] -3-carboxy - methyl-1-(3-theirproper)-2-pyrrolidinone.

Melting point ranging from 187aboutC (decomposition).

The value of Rf: a 0.27 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 12 6 1).

Calculated C 70,85 N 6,74 N compared to 8.26

Found, WITH 71,08 N 6,77 N 8,20

(14) (3S,5S)-5-[(4'-amidino-3'-chloro-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(3 - phenylpropyl)-2-pyrrolidinone.

Melting point ranging from 166aboutC (decomposition).

Calculated C 66,98 of 5.82 H N 8,08

Found, C 66,63 by 5.87 H N 8,07

(15) Dihydrate (3S,5S)-5-{[(4'-amidino-4-biphenylyl)carbonyl]aminomethyl} -3-Carbo - ximity-1-(3-phenylpropyl)-2-pyrrolidin Nona.

The melting point 208-214aboutC.

The value of Rf: to 0.40 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 6 3 1).

Calculated C 65,68 H 6,61 N OF 10.21

Found, C 65,48 H 6,20 N 9,99

(16) Semihydrate (3S,5S)-5-{[TRANS-4-(4-amidinophenoxy)cyclohexyl]oxymethyl}-3-carboxymethyl-1 -(3-ledenon.

The melting point 186-198aboutC.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 30 15 3).

Calculated C 69,57 H 7,65 N 8,39

Found, C 69,60 H 7,58 N SCORED 8.38

(17) (3S,5S)-5-{2-[(6-Amidino-2-afterburner)amino]ethyl}-3-carboxymethyl-1-(3-f tilh 2,5 H2O.

Melting point ranging from 166aboutWith sintering, 205aboutC (decomposition).

The value of Rf: 0,09 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 70 30 2).

Calculated C 63,84 H 6,84 N 10,27

Found, C, PHP 64.00 H 6,77 N 10,13

(18) Dihydrate (3S,5S)-5-[(6-amidino-2-naphthyl> the (decomposition).

The value of Rf: to 0.10 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 70 30 2).

Calculated C 64,35 H 6,56 N OF 10.72

Found, C 64,55 H 6,53 N 10,55

(19) Trihydrate (3S,5S)-5-[(7-amidino-2-afterburner)aminomethyl]-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

The melting point 195-207aboutC (decomposition).

The value of Rf: 0,38 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 62,21 H of 6.71 N 10,36

Found, C 61,98 H 6,75 N 10,55

(20) (3S,5S)-5-{2-[(7-Amidino-2-afterburner)amino]ethyl}-3-carboxymethyl-1-(3-f tilh 2,5 H2O.

The melting point 185-200aboutC (decomposition).

The value of Rf: 0,41 (silica gel RP8; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 63,84 H 6,83 N 10,27

Found, C 63,73 H 6,51 N 10,18

(21) (3S,5S)-{[TRANS-3-(4-amidinophenoxy)cyclobutyl]carbonylmethyl]-3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon x 1.5 H2O.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volumetric zootoxin Globotel]carbonylmethyl}-3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

(23) (3S,5S)-5-{2-[(CIS-3-|4-lidinopril|cyclobutyl)carbylamine]ethyl} -3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon x 1.5 H2O.

The value of Rf: 0,34 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

Calculated C 65,51 H 7,39 N 10,54

Found, C 65,04 H 7,24 N 10,26

(24) Dihydrate (3S,5S)-5-{2-[(TRANS-3-(|4-lidinopril|cyclobutyl)CARBONYLS-but]ethyl}-3-ka bokil) -2-pyrrolidinone.

The value of Rf: to 0.30 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 35 15 4).

Calculated C 64,43 H 7,45 N 10,36

Found, C 64,24 H 7,28 N 9,98

(25) (3S, 5S)-5-{ [3-(4-Amidinophenoxy)propyl]carbonylmethyl]-3-carboxyl - Teal-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.16 (silica gel; a mixture of methylene chloride, methanol and aqueous ammonia at a volume ratio of 4 to 1 by 0.2).

(26) Dihydrate (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-3-methyl - 1-(3-phenylpropyl)-2-pyrrolidinone.

Calculated C 67,27 of 6.96 H N A 7.85

Naide the roadways to the ratio of 4 to 1 0,25).

(27) Dihydrate (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-1-benzyl-carboxy - methyl-2-pyrrolidinone.

Calculated C 65,71 H 6,33 N 8,51

Found, C 66,08 H 6,13 N 8,48

(28) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(2 - phenylethyl)-2-pyrrolidinone.

Calculated C 68,69 H 6,38 N 8,58

Found, C 68,43 H between 6.08 N TO 8.41

(29) Hydrate (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(4 - phenylbutyl)-2-pyrrolidinone.

Calculated C to 69.61 H for 6.81 N 8,12

Found, C 69,29 H 6,57 N 8,35

(30) Dihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(4-phenyloxy Buti

Calculated C 65,32 H 6,76 N 7,62

Found, C 65,67 H 6,48 N 8,17

(31) (3S,5S)-5-{[4'-(n-Butylamino)-4-biphenylyl]oxymethyl}-3-carboxymethyl-1- (3-phenylpropyl)-2-pyrrolidinone x 1.5 H2O.

Calculated C 69,69 H 7,44 N 7,39

Found, C 69,42 H 7,37 N 7,35

(32) Hydrate (3S, 5S)-3-carboxymethyl-5-[(4'-methylamino-4-biphenylyl)oxymethyl] 1-(3-phenylpropyl)-2-pyrrolidinone.

Calculated C to 69.61 H for 6.81 N 8,12

Found C 69,22 H 6,88 N 7,98

(33) Dihydrate (3S,5S)-3-carboxymethyl-5-[(4'-isopropylamino-4-biphenylyl)the oxime - Tyl]-1-(3-phenylpropyl)-2-pyrrolidinone.

Calculated C 68,18 H 7,33 N 7,45

Found, C 67,87 H 7,47 to $ 7.91 N

(34) Semihydrate (3S,5S)-5-[(4'-amidino-4-b is BR>
Found, C 74,67 H 7,02 N 6,78

(35) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-(n-butyl)-3-carboxymethyl-1- (3-f

Calculated C 70,81 H 7,38 N 7,51

Found, C 70,54 H 7,33 N 7,47

(36 ) (3S,5S)-[(7-Amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-Fe - ylpropyl)-2-pyrrolidinone.

The melting point 226aboutC (decomposition).

(37) (3R,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(3-Hairdryer-Elpro saws)

The melting point of 225-227aboutC (decomposition).

(38) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)aminomethyl]-3-carboxymethyl-1-(3-Fe - ylpropyl)-2-pyrrolidinone.

The melting point of 208aboutC (decomposition).

(39) (3S,5S)-5-{[N-(4'-Amidino-4-biphenylyl)-N-methanesulfonyl]aminomethyl] -3-CT - boxymethyl-1-(3-phenylpropyl)-2-pyrrole-Denon.

Melting point above 200aboutWITH

Calculated C 64,03 H 6,10 N 9,96 S 5,70

Found, C 63,96 H 5,91 N 9,73 S ceiling of 5.60

(40) Hydrate (3S,5S)-5-{[N-(4'-amidino-4-biphenylyl)-N-acetyl]aminomethyl} -3-CT - Boxing - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

Calculated C 68,29 H 6,61 N 10,28

Found, C 68,57 H 6,62 N 10,15

(41) (3S,5S)-5-{[2-(|4-Lidinopril|amino)phenyl]carbonylmethyl}-3-carboxy - methyl-1-(3-phenylpropyl)-2-feast - religion.

Melting point ranging from 172aboutC (decomposition).

(42) (3S, 5S)-5-{ [4-(|4-Lidinopril|aminocarbonyl)phenyl]oxymethyl}-3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: to 0.45 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 2 1).

Calculated C 68,16 H 6,10 N OR 10.60

Found, C 68,46 to 6.19 H N 10,44

Mass spectrum: (M + H)+529.

(43) (3S,5S)-5-{[4-(|4-Lidinopril|carbylamine)phenyl]oxymethyl}-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

Melting point above 250aboutC.

The value of Rf: of 0.43 (silica gel; a mixture of metilenhloride, methanol and concentrated aqueous ammonia in a volume ratio 4 2 1).

Mass spectrum: (M + N)+529.

(44) (3S,5S)-5-{[4-(|4-Lidinopril|aminosulfonyl)phenyl]oxymethyl}-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidin he.

Melting point above 250aboutC.

The value of Rf: to 0.40 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 4 2 1).

Mass spectrum: (M + H)+565.

(45) (3S,5S)-5-{[4-(|3-Lidinopril|sulfenyl)phenyl]oxymethyl}-3-carboxymethyl-1- -(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: 0,14 (silica the>

Mass spectrum: (M + N)+518.

(46) (3S,5S)-5-{[4-(|3-Lidinopril|carbonyl)phenyl]oxymethyl}-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.21 (silica gel; a mixture of methylene chloride, ethanol and concentrated aqueous ammonia in a volume ratio 8 2 1).

Mass spectrum: (M + N)+514.

(47) (3S,5S)-5-{[4-(|3-Lidinopril|sulfonyl)phenyl]oxymethyl}-3-carboxymethyl-1- (3-phenylpropyl)-2-pyrrolidinone.

The melting point 205-207aboutC.

The value of Rf: of 0.20 (silica gel; a mixture of methylene chloride, ethanol and concentrated aqueous ammonia in a volume ratio 4 4 1).

Calculated C 63,37 H 5,69 N 7,63 S OF 5.83

Found, C 63,10 H 5,90 to 7.59 N S OF 5.92

Mass spectrum: (M + N)+550.

(48) (3S,5S)-5-{[4-(|3-Lidinopril|sulfinil)phenyl]oxymethyl}-3-carboxymethyl-1- (3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: of 0.25 (silica gel; a mixture of methylene chloride, ethanol and concentrated aqueous ammonia in a volume ratio 4 4 1).

Mass spectrum: (M + N)+534.

(49) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-1,3-bis-(carboxymethyl)-2-Pyrrhus Oleh 0,25 H2O.

The value of Rf: of 0.56 (silica gel; a mixture of methanol and conc is,55 N TO 9.57

Mass spectrum: (M + N)+426.

(50) Hydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-Carbo - ximity-1-[(ethylaminomethyl)methyl]-2 - pyrrolidinone.

The value of Rf: of 0.36 (silica gel; a mixture of methanol and concentrated aqueous ammonia in a volume ratio of 50 3). Calculated C 56,86 H 6,16 N 11,05 Cl 6,99 Found, C 56,87 H 6,39 of 11.26 N Cl 6,95

Mass spectrum: (M + H)+426.

(51) Semihydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-ka - boxymethyl-1- [(dimethylaminoethyl)methyl]-2-pyrrolidinone.

The value of Rf: to 0.24 (silica gel; a mixture of methanol and concentrated aqueous ammonia in a volume ratio of 50 3). Calculated C 57,89 H 6,07 N 11,25 Cl 7,11 Found, C 57,76 H between 6.08 N 11,34 Cl of 7.23

(52) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-1-[(benzylaminocarbonyl)methyl] -3-

Melting point above 200aboutC.

The value of Rf: of 0.37 (silica gel; a mixture of methanol and concentrated aqueous ammonia in a volume ratio of 50 2).

Mass spectrum: (M + N)+515.

(53) Hydrate hydrochloride (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -1-[(amino - carbonyl)methyl] -3-carboxymethyl-1-(3-Fe-ylpropyl)-2-pyrrolidinone.

Melting point above 200aboutC.

the 2 and 50). Calculated C 55,17 H 5,68 N 11,70 Cl 7,40 Found, C 57,35 H 5,68 N 11,88 Cl 7,20

Mass spectrum: (M + N)+425.

(54) Semihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-benzoyl-3-Carbo - ximity-pyrrolidine.

The melting point 234-237aboutC (decomposition).

The value of Rf: of 0.51 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 70 30 8).

Calculated C 69,51 H 6,05 N 9,01

Found, C 69,34 H 6,22 N 8,90

(55) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-IU - canalphone-pyrrolidine.

The melting point 266-268aboutC.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 100 10 4).

Calculated C 56,23 of 5.84 H N 9,37 S 7,15

Found, C 56,41 H 5,78 N 9,16 S OF 7.64

(56) Semihydrate (3S,5S)-1-acetyl-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3-Carbo - ximity-pyrrolidine.

The melting point 265-268aboutC (decomposition).

The value of Rf: 0,05 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 100 30 4).

Calculated C 65,33 H 6,48 N accounted for 10.39

Found, C 65,58 H 6,55 N 10,20

(57) Dihydrate (3S,5S)-5-agenie).

The value of Rf: to 0.30 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 100 30 4).

Calculated C 60,00 H 7,00 N 12,17

Found, C 60,18 H 6,98 N 12,34

(58) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(dimethy - aminosulfonyl)-pyrrolidin x 0,25 H2O.

The melting point of 278aboutC (decomposition).

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio of 100 30 4). Calculated C 56,81 H 6,18 N 12,05 S 6,89 Found, C 56,69 H 6,16 N 11,76 S 7,17

(59) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-methyl-pyrrol one

The value of Rf: or 0.57 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Mass spectrum: (M + H)+368.

(60) Hydrate (3R,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-2 - pyrrolidinone.

The melting point of 288aboutC (decomposition).

The value of Rf: 0,80 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 62,33 H 6,01 N 10,90

Found, C 62,53 H 5,90 N 11,03

(61) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)is 2">

The value of Rf: 0,74 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 63,14 of 6.31 H N 10,52

Found, C 63,31 H 6,53 N 10,41

(62) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(2-method xitil)-2-pyrrolidinone.

The melting point 230aboutC (decomposition).

The value of Rf: 0,75 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

(63) Semihydrate (3R,5R)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl - 2-pyrrolidinone.

The melting point 286-288aboutC (decomposition).

The value of Rf: to 0.63 (silica gel; a mixture of methanol and 10% aqueous solution of sodium chloride in a volume ratio of 6 to 4).

Calculated C 63,82 of 5.89 H N 11,16

Found, C 64,04 of 5.82 H N 10,89

(64) Semihydrate (3S,5S)-5-{2-[(4'-amidino-3-biphenylyl)amino]ethyl}-3-carboxyl - Teal-1-(3-phenylpropyl)-2-pyrrolidinone.

Calculated C 70,98 H 6,90 N 11,04

Found, C 70,72 H 6,99 N 10,86

(65) (3S,5S)-3-Carboxymethyl-5-{2-[(3'-guanidino-3-biphenylyl)amino]ethyl} -1-(3-Fe - ylpropyl)-2-pyrrolidinone x NH3x 2 H2O x 0.75 HCl.

The value of Rf: of 0.43 (silica gel; a mixture of methylene chloride, methanol and the concentration of the 4,29

(66) Hydrate semidetached (3S,5S)-5-{2-[(|3-amidino-4-biphenylyl|carbonyl)AMI - but]ethyl}-3-carboxymethyl-1-(3-phenylpro - saws)-2-pyrrolidinone.

The melting point of 214aboutC (decomposition).

Calculated C 66,20 H 6,54 N 9,96 Cl 3,15

Found, C 66,41 H 6,53 to 9.91 N Cl 3,22

(67) (3S,5S)-5-[(4'-amidino-3-methylsulphonyl-4-biphenylyl)oxymethyl]-3-carboxy - methyl-1-(3-phenylpropyl)-2-pyrrolidinone.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and aqueous ammonia at a volume ratio 2 1 0,25).

Mass spectrum: (M + N)+564.

(68) Hydrate (3S,5S)-5-[(4'-amidino-3-methylsulfinyl-4-biphenylyl)oxymethyl]-3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and aqueous ammonia at a volume ratio 2 1 0,25).

Calculated C 65,55 H 6.42 per of 7.64 N S OF 5.83

Found, C 65,70 H 6,58 of 7.64 N S 5,50

(69) Hydrate (3S,5S)-5-[(4'-amidino-3-methylsulfinyl-4-biphenylyl)oxymethyl]-3 - carboxymethyl-1-(3-phenylpropyl)-2-Pirro - ledenon.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 63,70 H 6,07 N 7,43 S 5,67

Found, C 63,55 of 6.31 H N 7,34 S 5,69

(70)dinona.

The value of Rf: 0,22 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25). Calculated C 61,44 H 5,78 N 9,88 S 5.66 Cl 3,13 Found, C 61,27 H 5,98 N 9,65 S 5,58 Cl 2,92

(71) (3S,5S)-5-{2-[(4-Amdinocillin)amino]ethyl}-3-carboxymethyl-1-(3-FeNi - propyl)-2-pyrrolidinone.

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Mass spectrum: (M + N)+477.

(72) (3S,5S)-5-[(4'-amidino-4-biphenylyl) oxymethyl]-3-carboxymethyl-1-[3-(3,4-acid) propyl]-2-pyrrolidinone x 1.5 H2O.

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 65,02 H 6,69 N 7,34

Found, C 65,20 H 6.73 x N 7,42

(73) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1- (4-hexyloxyphenyl)propyl]-2-pyrrolidin Nona.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 69,63 H 7,51 N OF 6.96

Found, C 69,54 to 7.67 H N 6,92

(74) Semihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-[3-the ü of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 71,97 H 7,32 N 7,63

Found, C 72,22 H 7,24 N 7,70

(75) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[3-(3-tripto of Medinan.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 63,03 H 5,64 N 7,35

Found, C 63,16 of 5.53 H N 7,41

(76) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[3-(2,4-dichl orfina.

The value of Rf: 0,41 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25). Calculated C 60,84 H 5,46 N 7,34 Cl KZT 12.39 Found, C 61,09 H 5,59 N 7,26 Cl 12,71

(77) Semihydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[3- (3-benzoylphenyl)propyl]-2-pyrrolidinone.

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 73,95 H 6,55 N 7,19

Found, C 73,85 H 6,79 N 6,90

(78) Hydrate (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-1-(4,4-diphenylbutane)-3 - carboxymethyl-2-pyrrolidinone.

The value of Rf: 0,22 (silica the x2">

Calculated C 72,51 to 6.43 H N 7,25

Found, C 72,73 H 6,61 N 7,29

(79) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[3-(4-IU - telesurveillance)propyl]-2-pyrrolidin-non x 1.5 H2O.

The value of Rf: to 0.28 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Calculated C 64,49 H 6,50 N 7,52 S 5,74

Found, C 64,62 H 6,34 N 7,35 of 5.84 S

(80) (3S,5S)-5-[(4'-Amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[3-(4-IU - tranformer)propyl]-2-pyrrolidin - non.

The value of Rf: to 0.30 (silica gel; a mixture of methylene chloride, methanol and concentrated aqueous ammonia in a volume ratio 2 1 0,25).

Mass spectrum: (M + N)+564.

(81)

Cyclic imino-derivatives of the formula

B X A Y E,

where A 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetylamino, C1C4-alkyl, substituted by two phenyl groups, cyclohexyl, naphthyl or phenyl, nexiam, the phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, C1C4-alkyl, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, and these substituents are not in position 1, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, benzylaminocarbonyl, pyrrolidinecarbonyl, piperidinylcarbonyl or morpholinoethyl, or carbonyl, substituted stands, phenyl, methoxymethyl, amino group, methylaminopropane, arylaminopoly, aminomethyl, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of A cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A; R2C1C4-alkyl, unsubstituted or substituted phenyl;

B amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano the ode from 2 to 5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y E unbranched C2C5-alkyl, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1, 2-Diocletian, carboxyla, phosphonopropyl, O-methylphosphono, Oh,O-dimethylphosphoric, oximation, alkoxycarbonyl with the total number of carbon atoms from 2 to 7, dimethylaminocarbonylmethyl, (2-morpholinoethyl)-oxycarbonyl, [2-(2-oxo-1-pyrrolidinyl)-ethyl] -oxycarbonyl, generalquartiermeister with 1 to 3 carbon atoms in the CNS group, which phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted C1C4-alkyl, diphenylolpropane, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

X1X2X3X4X5,

where X1bond, methylene or these can be an oxygen atom or sulfur, sulfonyl, imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -CONH-, -NHCO -, or-NH-SO2- or between ethylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of A and X5with residue B;

X2non-branched C2C4-alkylene, C2- C3-albaniles, and the double bond must not be adjacent to the heteroatom, phenylene, unsubstituted or substituted by fluorine, chlorine, bromine, stands, ethyl, trifluoromethyl, nitro-group, acetaminophe, methanesulfonylaminoethyl, methylsulfonyl, methylsulfinyl, methylsulfonyl, two methyl groups, C4C7-cycloalkyl or C7-bicycloalkyl;

X3bond or-CO-, -CONH, or NHCO, if X3not directly followed by a heteroatom or a triple bond of residue B, and-CO-, -CONH - or-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, non-branched C1C5-Ala is2together with X3and X4form a non-branched C3- C7-alkylen, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or C8- C11-cerealkiller;

X5communications,

a mixture of the isomers, enantiomers, diastereomers, or a physiologically tolerated salt having antithrombotic action.

 

Same patents:

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to the field of production of new derivatives pyrrolidine General formula

Y-Rwhere Y represents - (CH2)n-, whereby n = 0;

X is a hydrogen atom, halogen or lower alkyl group;

R is a phenyl group, phenyl group involved halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naftalina group, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl when n = 1;

X is H or halogen,

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y represents S(O)pwhere p = 0 or 2, -O - or-NH; X is hydrogen,

R-phenyl;

having anti-hypertensive activity

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 and R2 can be similar or different and mean branched or direct (C1-C6)-alkyl chain; R3 and R4 form in common a ring chosen from the group including pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl and comprising nitrogen atom to which they are bound, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing anti-hyperglycemic activity. Pharmaceutical composition comprises compound of the formula (I) as an active substance and an inert excipient. Invention provides using derivatives of biguanide possessing anti-hyperglycemic activity.

EFFECT: valuable medicinal property of derivatives.

9 cl, 2 tbl, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for purifying racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol that involves the following stages: (a) suspending racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol in ethanol and tetrahydrofuran mixture to form suspension wherein indicated mixture of ethanol and tetrahydrofuran has the volume ratio from 4:1 to 1:1; (b) stirring and heating the indicated suspension; (c) cooling the indicated suspension from the stage (b), and (d) collection of solid purified racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethocy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. Method provides preparing the end product containing less 0.1% of impurities.

EFFECT: improved purifying method.

11 cl, 11 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of the general formula (I) given below, physiologically acceptable salts of compounds of formula (I), where R3 denotes a hydrogen atom, as well as geometric isomers of compounds of formula (I), having RAR receptor (α, β, γ) inhibitory activity, use thereof to obtain pharmaceutical compositions and pharmaceutical compositions based on said compounds In formula (I), R1 denotes a hydrogen atom, an alkyl radical having 1-4 carbon atoms, or a CF3 radical; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or a straight alkyl or a radical having 1-10 carbon atoms; R4 and R5 denote a hydrogen atom or an alkyl radical having 1-3 carbon atoms, or alternatively, R4 and R5 denote a pyrrolidine ring, Y denotes two hydrogen atoms or an oxygen atom; Ar denotes a 1,4-phenyl ring; X denotes an oxygen or a single C-C bond, and A assumes values given in the claim.

EFFECT: obtaining novel compounds.

15 cl, 3 dwg, 56 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel aryl pyrrolidines of formula I:

, where X, which can be identical or different, denote halogen, halogen-C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen-C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, OH, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl-amino, C1-6alkoxycarbonyl amino groups, halogen-C1-6alkoxycarbonylamino; Y, which can be identical or different, denote halogen, halogen- C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen- C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, hydroxyl groups, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl amino, C1-6alkoxycarbonyl amino groups, halogen- C1-6alkoxycarbonyl amino; R denotes halogen- C1-6alkyl; m equals 0, 1, 2, 3, 4, 5; n equals 1, 2, 3, 4; G denotes a group: , where R1 and R2 each independently denotes H, unsubstituted C1-6alkyl, halogen- C1-6alkyl, -CH2R7;R3, R4 each independently denotes H; I equals 1, 2, 3; R5 denotes H; R6 denotes C1-6alkylcarbonyl, a group: G6 - G8:

b where k3 equals 0; k4 equals 0; R7 denotes an unsubstituted 6-member heteroaryl with one N; A denotes C, N.

EFFECT: compounds exhibit insecticidal activity, which enables use thereof in insect and/or tick control method.

7 cl, 13 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: device refers to new styrene derivatives with the structure formula A in the form of geometrical isomers or tautomers and their pharmaceutical acceptable salts. In structural formula (A) R1 represents hydrogen; R2 represents hydrogen or C1-C6alkyl; R3, R4, R5 and R6 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12; R7 represents hydrogen or C1-C6alkyl; R8 represents hydrogen; R9 represents hydrogen, C1-C6alkyl, or -C(=O)R13; R10 represents hydrogen or C1-C6alkyl; Z represents W-Y, wherein W represents -C(R14)(R15)-; Y represents -C(R16)(R17)-; each R12 independently represents hydrogen or C1-C6alkyl; each R13 independently represents C1-C6alkyl; R14 and R15 are identical or different, and independently specified in hydrogen, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OCH3 or -NH2; or R14 and R15 together form oxo; R16 and R17 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.

17 cl, 14 tbl, 143 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-methyl-N-{(1S)-1-phenyl-1-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-2,2-diphenylacetamide. Method involves the following steps: (a) interaction of N-substituted derivative of phenylglycine of the formula (I): , wherein R means -OR1, -SR1; R1 means A, benzyl, unsubstituted phenyl or phenyl, biphenyl or naphthyl mono- or disubstituted with halogen atom, -OA or (C1-C6)-alkyl; A means linear or branched (C1-C6)-alkyl; M means hydrogen atom (H) or a cation chosen from group comprising alkaline metals, earth-alkaline metals, ammonium or alkylammonium with compound of the formula (II): , wherein R2 means H, A, or with acid-additive salt of compound of the formula (II) of acids HCl, HBr, HJ, H2SO4, H3PO4, or with organic carboxylic acid to obtain compound of the formula (III): , wherein R and R2 have above given values; (b) synthesized compound is converted to compound of the formula (IV): , by reduction reaction that is converted optionally to acid-additive salt of acids HCl, HBr, HJ, H2SO4, H3PO4, or to salt of organic carboxylic acid, and (c) synthesized compound of the formula (IV) is subjected for interaction with activated carboxylic acid of the formula (V): , wherein R4 means F, Cl, Br, J, -OA or -O-CO-A to yield compound of the formula (VI): , that is converted to a corresponding acid-additive salt using inorganic acid chosen from group comprising HCl, HBr, HJ, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, ortho-phosphoric acid or using organic acid.

EFFECT: improved method of synthesis.

7 cl, 8 ex

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